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Role of the BMP signaling pathway in the pathogenesis of hereditary spastic paraplegias

Tuesday, October 25, 2011 — Poster Session II

Noon – 2:00 p.m.

Natcher Conference Center




  • R Singh
  • B Renvoise
  • J Stadler
  • C Blackstone


The hereditary spastic paraplegias (HSP) are a group of inherited neurological disorders characterized by a length-dependent axonopathy of the corticospinal tract causing progressive lower extremity weakness and spasticity. How mutations in these gene products result in disease pathogenesis is not entirely known. Some of the HSP related genes, including SPG6 (NIPA1), SPG4 ( Spastin) and SPG20 (Spartin) have been implicated in the bone morphogenetic protein (BMP) signaling pathway. BMP signaling is crucial for neuronal development and axonal function. Thus, this pathway is an attractive candidate for HSP pathogenesis. We investigated the reported inhibitory role of Spartin in the BMP pathway and its effects on BMP receptor trafficking based on its known interaction with IST1, a subunit of the Endosomal Sorting Complex Required for Transport complex. The availability of a SPG20 -/- mouse model provided us the opportunity to study neurons and observe phenotypic differences at the cellular level. In related studies, we are also investigating other HSP proteins implicated in endocytic mechanism, including the SPG15 protein spastizin that harbors a FYVE domain. Since a number of agents that inhibit BMP signaling have been developed, this pathway represents an attractive target for therapy.

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